Abstract: In the past decade a number of alternative vaping products have hit the market, rapidly gaining consumers among adults and, especially, adolescents. Electronic nicotine delivery systems or e-cigarettes (e-Cigs) have become the sought-after product due to the belief that they are much safer than traditional cigarettes. Moreover, tobacco smoking (TS) is associated with vascular endothelial dysfunction in a causative and dose dependent manner primarily related to the TS content of reactive oxygen species (ROS), nicotine, and oxidative stress (OS) -driven inflammation. Current scientific opinion considers OS-mediated pathways to play a major role in the pathogenesis of these disorders, especially stroke. Preclinical studies (and preliminary data presented herein) have shown that nicotine (the principal e-liquid's ingredient) can cause OS, exacerbation of cerebral ischemia and secondary brain injury. Likewise, chronic e-Cig vaping could be prodromal to cerebrovascular impairment and promote cerebrovascular conditions that favor the onset of stroke and post- ischemic brain injury, suggested by our initial findings. The health impact of e-Cig vaping is currently unknown and the limited research and dearth of regulatory guidelines for the content of the vaping solution for e-Cigs (various harmful compounds including aldehydes, nitrosamines etc. have been detected in the e-Cig vapors) has become a critical public and regulatory concern we also want to address with this research. Further, we and others have found that TS promotes glucose intolerance and increases the risk of developing type-2 diabetes mellitus (2DM) with which it shares other pathogenic traits including the high risk of cerebrovascular and neurological disorders like stroke via ROS generation, inflammation, and blood-brain barrier (BBB) impairment. Recent in vitro findings and preliminary data from our group, supports an additive release pattern of angiogenic, oxidative and inflammatory factors by BBB endothelial cells in response to hyperglycemia (HG) and/or stroke conditions with comcomitant exposure to cigarette smoke extracts (CSE), thus suggesting the involvement of common pathogenic modulators of BBB impairment. To this end, metformin (MF; a widely prescribed, firstline anti-diabetic drug) before and after stroke injury has been shown to reduces stress and inhibits inflammatory responses 88. Recent preliminary data revealed that MF activates counteractive mechanisms which drastically reduce TS toxicity at the level of the BBB. These beneficial effects have been shown to be mediated by MF activation of nuclear factor erythroid 2-related factor (Nrf2) 51. Our hypothesis is that excessive OS caused by TS and e- Cigs dysregulation of the cellular antioxidant response system is the linking underling mechanism prodromal to cerebrovascular toxicity and highten risk and/or severity of stroke In this respect we will: 1) Assess the potential cerebrovascular pathogenic impact of e-Cig vaping vs. TS through a side by side comparative study as per a recent call to action to investigate e-Cig toxicity by the regulatory agency and the Surgeon General; 2) Assess the molecular mechanisms (Nrf2/mitochondrial focused) driving TS-dependent impairment of the BBB and enhanced risk stroke and 3) Assess the viability and effectiveness of metformin (MF) to prevent/reduce TS and possibly e-Cig vaping-induced BBB damage and subsequent ischemic stroke injury. This is of outmost importance since chronic smoking carry high risks for cardiovascular diseases (CVD) and stroke but care treatment(s) only begins upon clinical manifestation of a disease. For chronic smokers (including early stage former smokers for whom the risk of stroke is still very high) there are no prophylactic options available.